Impact of Nicotine Exposure on Prostate Cancer Progression and Therapeutic Outcome
Abstract
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and second leading cause of cancer-related death in males in the United States. Over the past several decades, we have made significant progress in our understanding of PCa biology, however, a significant proportion of patients still continues to succumb to this disease, sooner or later, due to the failure of existing therapeutic options. Androgen deprivation therapy (ADT) remains the mainstay treatment for the advanced and metastatic PCa, but the tumors relapse in a castration-resistant (CR) form after an initial clinical response in most of the cases. CR PCa is highly aggressive and does not respond optimally to other alternative therapies as well, resulting in a poor prognosis. Thus, it is extremely imperative to characterize mechanisms underlying disease progression and therapy resistance, and use that knowledge to develop novel preventive and therapeutic interventions. Smoking is the single most modifiable risk factor for many human diseases, including cancer. This recognition has promoted the use of non-cigarette substitutes that contain nicotine to satiate addiction and provide the pleasing relaxed feeling, while having reduced levels of other cancer-causing toxic chemicals. Doubts about this notion, however, have been raised and the data show that nicotine can, in fact, affect several steps in the development of cancer. Epidemiological data strongly suggest an association of smoking with PCa aggressiveness, recurrence, and mortality, but experimental data implicating nicotine in PCa pathobiology is largely lacking. In our preliminary studies, we have made several novel findings that strongly suggest a pathobiological involvement of nicotine exposure in PCa aggressiveness and therapy resistance. We show that nicotine (i) promotes growth, aggressive phenotypes, and epithelial-to-mesenchymal transition of PCa cells; (ii) sustains the growth of castration-sensitive and augments the growth of castration-resistant PCa cells under androgen-deprived condition; (iii) imparts enzalutamide resistance; (iv) induces the expression of constitutively active AR-V7 splice variant form; (v) sustains the transcriptional activity of androgen-responsive promoter and PSA expression under androgen-deprived condition; and (vi) is associated with an enhanced phosphorylation of several pathologically relevant signaling proteins in PCa cells. Based on strong epidemiological suggestions from published data and our compelling preliminary findings, we put forward a novel hypothesis that nicotine exposure promotes prostate cancer progression and resistance to castration and enzalutamide therapy by sustaining aberrant activation of androgen receptor signaling. This hypothesis will be tested in three specific aims. In the first aim, we will use laboratory assays and preclinical models to establish the pathobiological significance of nicotine in aggressive PCa progression and therapy resistance. In the second aim, we will delineate the mechanisms underlying nicotine-induced molecular changes and their functional significance in mediating the effect of nicotine on prostate cancer phenotypes. In the third aim, we will examine the correlation of smoking behavior and direct nicotine exposure with molecular changes reported in laboratory studies. We will also study the correlative significance of smoking behavior, alone and in combination with observed molecular changes, with the clinico-pathological progression of PCa and time to PSA relapse. Resulting data from proposed innovative studies will provide experimental, mechanistic, pre-clinical and clinical support for an association of smoking and nicotine-exposure with PCa aggressiveness and therapy resistance. These findings will enhance our understanding of the biology of prostate cancer and in the longer term be useful for the development of novel approaches for PCa management.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210913
Entities
People
- Ajay Singh
Organizations
- United States Army
- University of South Alabama